Genetic polymorphisms in the glucuronosyltransferases 1A1, 1A8 and 1A9 in relation to pharmacokinetics of furosemide

Abstract

Background/Aims About 30% of the loop diuretic furosemide is eliminated via glucuronidation. According to in vitro data, uridine diphosphate glucuronosyltransferase (UGT) 1A8 may catalyze in this reaction but the quantitatively relevant isoenzyme in humans has not been unambiguously identified. We analyzed whether polymorphisms in UGT1A1, 1A8 and 1A9 are associated with the pharmacokinetics of furosemide. Methods In an open-label single dose study 93 healthy male volunteers got 80 mg furosemide and pharmacokinetics were measured over 24 hours after dosing. Polymorphisms in the UGT1A1, -1A8, and -1A9 genes were analyzed by pyrosequencing. Results Seven polymorphisms distributed over the UGT1A1 gene and 2 polymorphisms in the UGT1A8 and UGT1A9 genes were analyzed in correlation with furosemide total oral clearance. One C/T polymorphism in the intron 3 of the UGT1A1 gene was associated with furosemide clearance (p= 0.024) with a mean of 16.7, 17.2, and 22.3 L/h in CC, CT, and TT carriers, respectively. One A/T polymorphism at position −276 in the UGT1A9 promotor was also associated (p=0.049) with mean clearance of 18.0, 14.1, and 13.0 L/h in A/A, A/T, and T/T carriers. Significant associations with furosemide drug actions were not found. Conclusions There was a large interindividual kinetic and dynamic variability of furosemide in healthy volunteers and genetic polymorphisms in UGT enzymes may partially explain this variability. Clinical Pharmacology & Therapeutics (2005) 77, P34–P34; doi: 10.1016/j.clpt.2004.12.021